Inhibiting early-stage events in HIV-1 replication by small-molecule targeting of the HIV-1 capsid

Sandhya Kortagere, Navid Madani, Marie K. Mankowski, Arne Schön, Isaac Zentner, Gokul Swaminathan, Amy Princiotto, Kevin Anthony, Apara Oza, Luz Jeannette Sierra, Shendra R. Passic, Xiaozhao Wang, David M. Jones, Eric Stavale, Fred C. Krebs, Julio Martín-García, Ernesto Freire, Roger G. Ptak, Joseph Sodroski, Simon CocklinAmos B. Smith

Research output: Contribution to journalArticle

Abstract

The HIV-1 capsid (CA) protein plays essential roles in both early and late stages of virl replication and has emerged as a novel drug target. We report hybrid structure-based virtual screening to identify small molecules with the potential to interact with the N-terminal domain (NTD) of HIV-1 CA and disrupt early, preintegration steps of the HIV-1 replication cycle. The small molecule 4,4=-[dibenzo[b,d]furan-2,8-diylbis(5-phenyl-1H-imidazole-4,2-diyl)]dibenzoic acid (CK026), which had anti-HIV-1 activity in single- and multiple-round infections but failed to inhibit viral replication in peripheral blood mononuclear cells (PBMCs), was identified. Three analogues of CK026 with reduced size and better drug-like properties were synthesized and assessed. Compound I-XW-053 (4-(4,5-diphenyl-1H-imidazol-2-yl)benzoic acid) retained all of the antiviral activity of the parental compound and inhibited the replication of a diverse panel of primary HIV-1 isolates in PBMCs, while displaying no appreciable cytotoxicity. This antiviral activity was specific to HIV-1, as I-XW-053 displayed no effect on the replication of SIV or against a panel of nonretroviruses. Direct interaction of I-XW-053 was quantified with wild-type and mutant CA protein using surface plasmon resonance and isothermal titration calorimetry. Mutation of Ile37 and Arg173, which are required for interaction with compound I-XW-053, crippled the virus at an early, preintegration step. Using quantitative PCR, we demonstrated that treatment with I-XW-053 inhibited HIV-1 reverse transcription in multiple cell types, indirectly pointing to dysfunction in the uncoating process. In summary, we have identified a CAspecific compound that targets and inhibits a novel region in the NTD-NTD interface, affects uncoating, and possesses broad-spectrum anti-HIV-1 activity.

Original languageEnglish (US)
Pages (from-to)8472-8481
Number of pages10
JournalJournal of virology
Volume86
Issue number16
DOIs
StatePublished - Aug 2012

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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  • Cite this

    Kortagere, S., Madani, N., Mankowski, M. K., Schön, A., Zentner, I., Swaminathan, G., Princiotto, A., Anthony, K., Oza, A., Sierra, L. J., Passic, S. R., Wang, X., Jones, D. M., Stavale, E., Krebs, F. C., Martín-García, J., Freire, E., Ptak, R. G., Sodroski, J., ... Smith, A. B. (2012). Inhibiting early-stage events in HIV-1 replication by small-molecule targeting of the HIV-1 capsid. Journal of virology, 86(16), 8472-8481. https://doi.org/10.1128/JVI.05006-11